Stress in Head and Neck Cancer: A Study of the Antagonist(s) and Agonist(s) of the Glucocorticoid Receptor

Abstract

Background: The diagnosis of head and neck cancer (HNC) entails multiple stressors. The physical, emotional, and financial challenges associated with the disease generate stress responses and result in the production of stress hormones. The release of cortisol and its effect on tumour progression via glucocorticoid signalling has become an area of interest in cancer studies. The current evidence indicates increased circulating levels of cortisol in patients with HNC. The role of cortisol has been investigated in DNA damage, cell proliferation and its effect on chemotherapy. Mifepristone, the glucocorticoid receptor (GR) antagonist is also being widely investigated as an anti-cancer agent in many types of cancer. The effect of cortisol and mifepristone in terms of cell migration and the underlying signalling pathways is scarcely reported for HNC.

Aim: The aim of this project was to study the expression of the GR, effect of its agonist cortisol and the antagonist mifepristone on migration, proliferation and the underlying PI3K-Akt and MAPK signalling pathways in normal and oral cancer cell lines.

Methodology: In vitro methodology was employed, including cell scatter, gap closure and Boyden chamber assays to study cell migration, MTT to study cell proliferation, Western blot and immunocytochemistry to study the localisation of phosphorylated Akt, phosphorylated p44/42 MAPK, GR and EMT markers. Adult human skin keratinocytes (HaCaT) were used as normal cells, oral adenosquamous cell carcinoma (TYS) and squamous cell carcinoma of tongue (SAS-H1) as oral cancer cells.

Results: The expression of GR was increased in oral cancer cells. Cortisol stimulated while high concentrations of mifepristone suppressed cell migration and proliferation via the involvement of PI3K-Akt and MAPK signalling pathways in oral cancer cells. Signalling pathway specific inhibitors reduced cortisol-induced effects. The presence of cortisol decreased the effectiveness of signalling pathway specific inhibitors and amplified the effect of EGF on migration of oral cancer cells.

Conclusion: These findings suggest the direct impact of the stress hormone cortisol on disease and show the consequences of the presence of cortisol alongside growth factors and inhibitors. This highlights the importance of stress management as part of a global cancer treatment plan in limiting disease progression and positively influencing outcomes.

Date of Award	2024
Original language	English
Awarding Institution	University of Dundee
Supervisor	Ian Ellis (Supervisor), Sarah Jones (Supervisor) & Simon Shepherd (Supervisor)